TY - JOUR
T1 - IQGAP1 scaffold-MAP kinase interactions enhance multiple myeloma clonogenic growth and self-renewal
AU - Gocke, Christian B.
AU - McMillan, Ross
AU - Wang, Qiuju
AU - Begum, Asma
AU - Penchev, Vesselin R.
AU - Ali, Syed A.
AU - Borrello, Ivan
AU - Huff, Carol Ann
AU - Matsui, William
N1 - Funding Information:
This study was supported by grants from the NIH (P30 CA006973), NCI (R01CA174951; to W.H. Matsui), National Heart, Lung, and Blood Institute (T32HL007525; to C.B. Gocke), Conquer Cancer Foundation Young Investigator Award (to C.B. Gocke), and the Hopkins-Allegheny Health Network Cancer Research Fund (to W.H. Matsui). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Publisher Copyright:
© 2016 American Association for Cancer Research.
PY - 2016/11
Y1 - 2016/11
N2 - Despite improved outcomes in newly diagnosed multiple myeloma, virtually all patients relapse and ultimately develop drug-resistant disease. Aberrant RAS/MAPK signaling is activated in the majority of relapsed/refractory multiple myeloma patients, but its biological consequences are not fully understood. Selfrenewal, as defined by the long-term maintenance of clonogenic growth, is essential for disease relapse, and we examined the role of RAS/MAPK activation on multiple myeloma self-renewal by targeting IQ motif-containing GTPase-activating protein 1 (IQGAP1), an intracellular scaffold protein required for mutant RAS signaling. We found that loss of IQGAP1 expression decreased MAPK signaling, cell-cycle progression, and tumor colony formation. Similarly, a peptide mimicking the WW domain of IQGAP1 that interacts with ERK inhibited the clonogenic growth and self-renewal of multiple myeloma cell lines and primary clinical specimens in vitro as well as tumor-initiating cell frequency in immunodeficient mice. During multiple myeloma progression, self-renewal may be enhanced by aberrant RAS/MAPK signaling and inhibited by targeting IQGAP1.
AB - Despite improved outcomes in newly diagnosed multiple myeloma, virtually all patients relapse and ultimately develop drug-resistant disease. Aberrant RAS/MAPK signaling is activated in the majority of relapsed/refractory multiple myeloma patients, but its biological consequences are not fully understood. Selfrenewal, as defined by the long-term maintenance of clonogenic growth, is essential for disease relapse, and we examined the role of RAS/MAPK activation on multiple myeloma self-renewal by targeting IQ motif-containing GTPase-activating protein 1 (IQGAP1), an intracellular scaffold protein required for mutant RAS signaling. We found that loss of IQGAP1 expression decreased MAPK signaling, cell-cycle progression, and tumor colony formation. Similarly, a peptide mimicking the WW domain of IQGAP1 that interacts with ERK inhibited the clonogenic growth and self-renewal of multiple myeloma cell lines and primary clinical specimens in vitro as well as tumor-initiating cell frequency in immunodeficient mice. During multiple myeloma progression, self-renewal may be enhanced by aberrant RAS/MAPK signaling and inhibited by targeting IQGAP1.
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U2 - 10.1158/1535-7163.MCT-16-0323
DO - 10.1158/1535-7163.MCT-16-0323
M3 - Article
C2 - 27573425
AN - SCOPUS:84995421887
VL - 15
SP - 2733
EP - 27339
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
SN - 1535-7163
IS - 11
ER -